Clinical Update

VIDEO AVAILABLE Intracameral What the Evidence Shows

by linda roach, contributing writer interviewing david f. chang, md, randy j. epstein, md, and neal h. shorstein, md

hould more cataract surgeons Making the Case set aside their doubts and add intracameral injec- tions to their endophthal- mitis-prevention routines? U.S.S holdouts on the issue lost one of their chief objections to this mode of prophylaxis at the beginning of 2013, when California researchers confirmed the results of a 2007 landmark Euro- pean study. The U.S. study found that an intra- cameral injection of cefuroxime at the end of surgery was effective at prevent- ing ,1 as it was in the European trial.2 When the California team analyzed more than 16,000 cases of , they found that the rate of endophthalmitis dropped Recent evidence indicates that the rate of endophthalmitis (shown here) drops 22-fold when intracameral antibiotics substantially when intracameral antibiotics are used. were used. “The take-home message is that paid to the practice of injecting intra- compounding. “There is no commer- there is now clear evidence that intra- cameral antibiotics to prevent endoph­ cially available, FDA-approved drug cameral antibiotics are a benefit,” said thalmitis. “As more clinical studies are right now. And that’s really the huge study coauthor Neal H. Shorstein, MD, published, interest among U.S. sur- hurdle,” Dr. Shorstein said. “I think at with Kaiser Permanente. geons is definitely increasing.” this point the skeptics are more con- Surgeons who remain skeptical cerned about the compounding issue Increasing Acceptance? about this method of preventing infec- than about the efficacy.” Many American cataract surgeons tion might want to reevaluate their “Of all of the endophthalmitis pro- have resisted the European study’s stance, said Randy J. Epstein, MD, at phylaxis measures in use, preoperative conclusions as inapplicable because of Rush University. Betadine [povidone-iodine] solution procedural differences between Europe “I think the European and Califor- and direct intracameral antibiotic in- and the United States. Instead, they nia studies have provided us with am- jection are supported by the strongest have opted for topical prophylaxis, ple evidence of the safety and efficacy evidence,” Dr. Chang said. “However, despite weaker evidence of efficacy.3 of this route of antibiotic administra- in order to begin injecting cefuroxime But the latest data may bring about a tion,” said Dr. Epstein. into the anterior chamber, the surgeon change, observers say. first must find a way to formulate it David F. Chang, MD, at the Univer- Safety Issues properly and safely, such as using a sity of California, San Francisco, said Compounding concerns. The problem well-run compounding pharmacy.”

bcsc vol. 11/karla j. john, md he has noticed new attention being with using cefuroxime? In a word: Since his study was published, Dr.

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Shorstein said, he has been kept busy Moxifloxacin: Logical and easy. responding to e-mails and phone calls Prevent Toxic Errors Topical moxifloxacin (Vig­amox 0.5 from ophthalmologists. Many of the percent), which is widely used in the Antibiotic solutions prepared for in- calls he has fielded have come from United States to treat infections of the tracameral injection should be free of surgery centers, where staff members ocular surface, has characteristics that preservatives or other additives, Dr. “want to know how we compound the make it attractive to surgeons who are Shorstein warned. antibiotics, because it wasn’t in the leery of compounded cefuroxime but An outbreak of toxic anterior seg- original article.” convinced that injecting an antibiotic ment syndrome (TASS) was reported As it happens, Dr. Shorstein and into the chamber is beneficial, Dr. Ep- after a compounding pharmacist— his colleagues have an advantage that stein said. who was diluting topical moxifloxacin many cataract surgeons do not: an in- “Since we have a [formulation of] for intracameral use—used Moxeza, house compounding pharmacy that moxifloxacin that is nonpreserved, this which contains a preservative and they trust to perform the painstaking is the path of least resistance,” he said. other additives, instead of Vig­amox, process of preparing the medication (See “Prevent Toxic Errors.”) which is preservative free.1 for ocular use. At least one study has reported Proper dilution of cefuroxime also Strict protocol for use. Cefuroxime, that moxifloxacin, a broad-spectrum, is essential (1 mg/0.1 mL), to avoid which is a broad-spectrum cepha- fourth-generation fluoroquinolone, is an containing losporin, is approved and labeled in well tolerated in the anterior segment.5 as much as 100 times the recom- the United States for intravenous and Moreover, surgeons can trust that an mended dose. TASS and permanent intramuscular use. It is sold to phar- unopened bottle of Vigamox will be visual loss have been reported after macies in bulk powder form and, when both sterile and properly formulated, dosing errors.2-4 reconstituted as recommended, pro- Dr. Epstein said. duces a solution of 750 mg of drug per The process of sourcing and han- 1 Mamalis N. “TASS associated with intra- 7.5 to 8 mL. dling the medication in the OR is not cameral antibiotic injection,” May 8, 2013. In contrast, the standard intracam- difficult, he added. “I order that the www.ascrs.org/Press-Releases; accessed eral injection volume is 0.1 mL, con- patient be given preoperative Vigamox Sept. 27, 2013. taining 1 mg of cefuroxime. Moreover, on the table, just prior to surgery. That 2 Olavi P. Acta Ophthalmologica. 2012;90(2): a portion of the high-concentration way they have their own, brand-new, e153-154. solution must be withdrawn and di- sterile bottle that’s been ordered for 3 Qureshi F, Clark D. J Cataract Refract Surg. luted a second time with nonpreserved them. The scrub nurse withdraws 2011;37(6):1168-1169. normal saline, then transferred 1 mL some in a sterile manner prior to eye- 4 Delyfer MN et al. J Cataract Refract Surg. at a time into single-use vials for the drop administration.” 2011;37(2):271-278. operating room. All steps require strict If the center where he will be oper- aseptic technique and a laminar flow ating balks at paying for the drug, Dr. hood, Dr. Shorstein said. the conclusion of cataract surgery,” Dr. Epstein writes a prescription for it pre- Single-dose solution. In Europe, Chang said. “I have used intracameral operatively and instructs the patient concerns about the risks of dilution er- for more than 12 years. At to bring the unopened bottle to the ror and microbial contamination dur- the conclusion of surgery, I inject 0.1 OR on the day of surgery. “The nurses ing this lengthy process were eased last mL [1 mg] of diluted vancomycin that open that bottle in a sterile manner, year, when a French company began is mixed by the nursing staff in the OR and the scrub nurse withdraws 0.2 cc selling single-dose cefuroxime, called on the morning of surgery.” from the bottle into a syringe, using Aprokam, for intracameral injection. What about fears that using a last- sterile technique. The eyedrops are (The drug is also sold under the names ditch antibiotic in this way might in- administered preoperatively. Then, at Prokam and Aprok.) crease bacterial resistance in exposed the end of the case, I administer 0.05 Dr. Chang and others have called ocular bacteria? “Because such a tiny cc intracamerally from the sterile sy- publicly for a U.S. drug company to dose of vancomycin is injected into a ringe.” The patient is given the rest of follow suit; so far, however, none has sterile and isolated ocular compart- the bottle to take home. taken this step. ment, I believe that the theoretical risk More than 4,000 eyes after he began of inducing drug resistance should be this routine, Dr. Epstein has this ver- Alternatives to Cefuroxime tiny,” Dr. Chang said. “The Liverpool dict: So far, so good. “I’ve never had a Vancomycin: Effective against MRSA. study provides good evidence that ef- patient who has received intracameral “A frequently overlooked human phar- fectively high aqueous levels are sus- moxifloxacin develop endophthalmitis macokinetics study from Liverpool4 tained well beyond 24 hours with this thus far.” n demonstrated surprisingly high and dosage, and vancomycin does cover” prolonged aqueous levels of vancomy- methicillin-resistant Staphylococcus 1 Shorstein NH et al. J Cataract Refract Surg. cin following intracameral injection at aureus (MRSA). 2013;39(1):8-14.

26 december 2013 Cataract

Prophylaxis With Intracameral Cefuroxime

Rationale for Use • Cefuroxime is a broad-spectrum cephalosporin. It is already well char- acterized because it is used perioperatively for prophylaxis in other surgical procedures (such as heart surgery and hysterectomy). • Intracameral injection at the conclusion of cataract surgery proved effica- cious in a large, prospective European trial. This was supported by multiple large, comparative studies overseas and a recent U.S. study. • Evidence of efficacy for alternative drugs for intracameral injection (moxi- floxacin and vancomycin) is weaker.

Dosage • 1 mg of cefuroxime in 0.1 mL

Preparation1 • A normal-strength solution of cefuroxime for injection is many times too concentrated for use in the eye. An exacting two-step dilution process, un- der sterile conditions, is required to prepare it for intracameral injection. • For safety, dilutions should be performed with aseptic technique and under a laminar flow hood. For many surgeons, this will require an off-site compounding pharmacy. • The compounding pharmacy should meet the sterile compounding guide- lines of the U.S. Pharmacopeial Convention2 and undergo regular inspections.

Injection Protocol • 100 percent of cataract patients at Dr. Shorstein’s hospital receive an intracameral antibiotic injection at the end of surgery. • 1 mL is prepared for each patient on the morning of surgery; 0.2 mL of this is drawn into a 1 mL tuberculin syringe, with an angled 27-gauge can- nula, in the sterile field. • After IOL placement and stromal hydration, the surgeon injects half of the syringe’s contents—0.1 mL (1 mg of drug)—into the anterior chamber through the paracentesis. • If the eye softens, requiring additional stromal hydration, the surgeon delivers the second 0.1 mL dose of the drug, using the remainder in the syringe. • If the remainder is not needed, it is discarded, as is the vial from which the medication was drawn.

Comments • This is an off-label use. • The complex, two-step dilution process raises the risks of bacterial con- tamination and dilution errors. • When patients are allergic to cephalosporins, moxifloxacin is Dr. Shor- stein’s first choice as a substitute, followed by vancomycin.

1 For detailed information about preparation of cefuroxime, moxifloxacin, and vancomycin for intracameral injection, see a letter by Dr. Shorstein and Ellen T. Nguyen, PharmD, in the Journal of Cataract and Refractive Surgery (in press, November 2013). 2 Pharmaceutical compounding—sterile preparations (general chapter 797). In: Second Supplement of USP 31-NF 26, and the Pharmacists’ Pharmacopeia (2nd edition). Rockville, Md.: United States Pharmacopeial Convention; 2008. S2/33-S2/69. Available at: www.usp.org/sites/default/files/usp_pdf/EN/products/usp2008p2supplement2.pdf.

2 Endophthalmitis Study Group, European David F. Chang, MD, practices in Los Altos, Neal H. Shorstein, MD, practices in Walnut Society of Cataract and Refractive Surgeons. Calif., and is a clinical professor of ophthal- Creek, Calif., with Kaiser Permanente. He also J Cataract Refract Surg. 2007;33(6):978-988. mology at the University of California, San serves as the associate chief of quality for Kai- 3 Gower EW et al. Cochrane Database Syst Francisco. He reports no related financial ser Permanente’s Northern California Diablo Rev. 2013 July 15;7:CD00634. interests. Service Area. He reports no related financial 4 Murphy CC et al. Br J Ophthalmol. 2007; Randy J. Epstein, MD, is professor of ophthal- interests. 91:1350-1353. mology at Rush University Medical Center in 5 Lane SS et al. J Cataract Refract Surg. Chicago and CEO of Chicago Consul- MORE ONLINE: For a video on in- 2008;34(9):1451-1459. tants. He is a consultant for Alcon. jection protocol, see www.eyenet.org.

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